The USP46 deubiquitylase complex increases Wingless/Wnt signaling strength by stabilizing Arrow/LRP6.

Autor: Spencer ZT; Department of Molecular and Systems Biology and the Dartmouth Cancer Center, Geisel School of Medicine, Dartmouth College, Hanover, NH, 03755, USA., Ng VH; Department of Cell and Developmental Biology, Vanderbilt University, Nashville, TN, 37232, USA., Benchabane H; Department of Molecular and Systems Biology and the Dartmouth Cancer Center, Geisel School of Medicine, Dartmouth College, Hanover, NH, 03755, USA., Siddiqui GS; Department of Molecular and Systems Biology and the Dartmouth Cancer Center, Geisel School of Medicine, Dartmouth College, Hanover, NH, 03755, USA., Duwadi D; Department of Molecular and Systems Biology and the Dartmouth Cancer Center, Geisel School of Medicine, Dartmouth College, Hanover, NH, 03755, USA., Maines B; Department of Molecular and Systems Biology and the Dartmouth Cancer Center, Geisel School of Medicine, Dartmouth College, Hanover, NH, 03755, USA., Bryant JM; Department of Cell and Developmental Biology, Vanderbilt University, Nashville, TN, 37232, USA., Schwarzkopf A; Department of Cell and Developmental Biology, Vanderbilt University, Nashville, TN, 37232, USA., Yuan K; Department of Molecular and Systems Biology and the Dartmouth Cancer Center, Geisel School of Medicine, Dartmouth College, Hanover, NH, 03755, USA., Kassel SN; Department of Cell and Developmental Biology, Vanderbilt University, Nashville, TN, 37232, USA., Mishra A; Department of Molecular and Systems Biology and the Dartmouth Cancer Center, Geisel School of Medicine, Dartmouth College, Hanover, NH, 03755, USA., Pimentel A; Department of Molecular and Systems Biology and the Dartmouth Cancer Center, Geisel School of Medicine, Dartmouth College, Hanover, NH, 03755, USA., Lebensohn AM; Laboratory of Cellular and Molecular Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, 20892, USA., Rohatgi R; Department of Biochemistry, Stanford University School of Medicine, Stanford, CA, 94305, USA., Gerber SA; Department of Molecular and Systems Biology and the Dartmouth Cancer Center, Geisel School of Medicine at Dartmouth, Lebanon, NH, 03766, USA., Robbins DJ; Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC, 20057, USA., Lee E; Department of Cell and Developmental Biology, Vanderbilt University, Nashville, TN, 37232, USA. ethan.lee@vanderbilt.edu., Ahmed Y; Department of Molecular and Systems Biology and the Dartmouth Cancer Center, Geisel School of Medicine, Dartmouth College, Hanover, NH, 03755, USA. yfa@dartmouth.edu.
Jazyk: angličtina
Zdroj: Nature communications [Nat Commun] 2023 Oct 05; Vol. 14 (1), pp. 6174. Date of Electronic Publication: 2023 Oct 05.
DOI: 10.1038/s41467-023-41843-0
Abstrakt: The control of Wnt receptor abundance is critical for animal development and to prevent tumorigenesis, but the mechanisms that mediate receptor stabilization remain uncertain. We demonstrate that stabilization of the essential Wingless/Wnt receptor Arrow/LRP6 by the evolutionarily conserved Usp46-Uaf1-Wdr20 deubiquitylase complex controls signaling strength in Drosophila. By reducing Arrow ubiquitylation and turnover, the Usp46 complex increases cell surface levels of Arrow and enhances the sensitivity of target cells to stimulation by the Wingless morphogen, thereby increasing the amplitude and spatial range of signaling responses. Usp46 inactivation in Wingless-responding cells destabilizes Arrow, reduces cytoplasmic accumulation of the transcriptional coactivator Armadillo/β-catenin, and attenuates or abolishes Wingless target gene activation, which prevents the concentration-dependent regulation of signaling strength. Consequently, Wingless-dependent developmental patterning and tissue homeostasis are disrupted. These results reveal an evolutionarily conserved mechanism that mediates Wnt/Wingless receptor stabilization and underlies the precise activation of signaling throughout the spatial range of the morphogen gradient.
(© 2023. Springer Nature Limited.)
Databáze: MEDLINE
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